Commercial

The US Food and Drug Administration (FDA) Center for Devices and Radiologic Health (CDRH) is among one of several groups leading development of a framework for evaluating the rapidly increasing number of digital therapeutics and mobile-based health applications anticipated to reach market as part of the expanding digital health innovation space. The International Medical Device Regulators Forum, a consortium of medical device regulators from around the world, led by the FDA, distinguishes between 1) software in a medical device, and 2) software as a medical device (SaMD). The FDA is not enforcing compliance for lower risk mobile apps, such as those that address general wellness, nor are they addressing technologies that are purposed to receive, transmit, store, or display data from established medical devices.

Digital therapeutics and mobile software addressed herein are those in which the ancillary hardware device is intended to function solely in conjunction with the mobile device application with the function of becoming a regulated medical device by performing user-specific analysis and providing individualized-specific diagnosis, or treatment recommendations. These types of functions are similar to or perform the same function as those types of software devices that have been previously cleared or approved by appropriate regulatory bodies.

Several of the products evaluated as a PDT,, particularly those that operate with an ancillary hardware medical device, may be intended to replace a service traditionally rendered in a healthcare setting. Use of these therapies/apps should not be substantiated primarily for the convenience of the individual, prescribing clinician, caregiver, or other healthcare provider (e.g., in cases where appropriate alternatives for the indicated health service(s) are geographically accessible, and/or when the individual has concurrent ambulatory or hospital care needs). However, use may be appropriate when in accordance with generally accepted standards of medical practice, the application has been proven materially to be as beneficial as the established alternative, and credible scientific evidence permits conclusions regarding the impact of the technology on clinically relevant health outcomes.

Provider-prescribed, FDA cleared or approved, digital therapeutics or mobile-based health management applications (not an all-inclusive list):

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BlueStar®Rx System

BlueStar®Rx System is a digital health platform for individuals with type 1 or type 2 diabetes that provides tailored guidance driven by artificial intelligence and is focused on six critical dimensions of chronic disease care, which apply to diabetes as well as many other conditions like blood pressure, pre-diabetes, and heart failure. The platform utilizes coaching messages (motivational, behavioral, educational) based on real-time blood glucose values. The software is for use on mobile phones or personal computers. It also includes an insulin dose calculator that allows participants to calculate a dose of their prescribed insulin regimen for a given amount of carbohydrates and/or blood glucose value. The software also now includes an Insulin Adjustment Program (IAP) that calculates appropriate long-acting basal insulin doses for titrating insulin levels based on configuration by a healthcare provider (the healthcare provider must activate and configure the IAP for patient-specific parameters). According to manufacturer website, the BlueStar Rx System is not intended to replace the care provided by a licensed healthcare professional, including prescriptions, diagnosis, or treatment.

Agarwal et al. (2019) evaluated the BlueStar mobile app to determine if app usage resulted in improved hemoglobin A1c (HbA1c) in real-life clinical setting. The study involved a multicenter pragmatic randomized controlled trial (RCT) consisting of 110 participants randomly assigned to the immediate treatment group (ITG) receiving the intervention for 6 months, and 113 participants randomly assigned to the wait-list control (WLC) group receiving usual care for the first 3 months and then receiving the intervention for 3 months. The primary outcome was glycemic control measured by HbA1c levels at 3 months and secondary outcomes determined intervention impact on diabetes self-management, experience of care, and self-reported health utilization using validated scales (i.e., the Problem areas in Diabetes, the Summary of Diabetes Self-Care Activities, and the EuroQo1-5D). The BlueStar mobile app captured the intervention usage data. The results did not show evidence of intervention impact on HbA1c levels at 3 months (mean difference [ITG-WLC] -0.42, 95% confidence interval [CI] -1.05 to 0.21; P=0.19). Additionally, no intervention effect on secondary outcomes measuring diabetes self-efficacy, quality of life, and healthcare utilization behaviors was observed. Significant variation in app usage by site was noted such that participants from one site logged in to the app a median of 36 days over 14 weeks (interquartile range [IQR] 10.5 to 124), whereas participants at another study location showed a notable decrease in app usage (median 9; IQR 6 to 51). The results demostrated that there was no difference between intervention and control arms for the primary outcome of glycemic control measured by HbA1c levels, and the low usage of the app among participants warrants further study of user- and site-specific factors that could increase app usage.

Canvas Dx™ autism diagnosis aid

Canvas Dx is a prescription-only device intended for use by healthcare providers as an aid in the diagnosis of autism spectrum disorder (ASD) for individuals ages 18 months through 72 months who are at risk for developmental delay based on concerns of a parent, caregiver, or healthcare provider. The device is not intended for use as a stand-alone diagnostic device but as an adjunct to the diagnostic process.

The evidence for Canvas Dx includes a single prospective study of clinical validity. Relevant outcomes are test validity, change in disease status, functional outcomes, and quality of life. Results of the study reported that Canvas Dx outperformed conventional autism screeners both in area under the curve (AUC), sensitivity, and specificity. Several limitations were identified. The major limitation is the lack of clarity on how the test fits into the current diagnostic pathway. Diagnosis of ASD in the United States generally occurs after completion of two steps: developmental screening followed by comprehensive diagnostic evaluation if screened positive. To evaluate the utility of the test, an explication of how the test would be integrated into the current recommended screening and diagnostic pathway is needed. Neither the manufacturer's website nor the FDA-cleared indication is explicit on how the test fits into the current pathway. It is unclear whether the test is meant to be used as an add-on test to established comprehensive diagnostic evaluation tests or if it could replace existing comprehensive diagnostic evaluation tests among a population of children at risk for developmental delay for confirmatory diagnosis of ASD. In addition, there is also a potential of "off-label" use of this test in the general population, either as a screening test or a diagnostic test. Second, the manufacturer asserts that Canvas Dx is intended to be used by a primary care physician to aid in the diagnosis of ASD, but the published study on clinical validity used a specialist rather than a primary care physician to complete the clinical questionnaire module. This is likely to result in higher sensitivity and specificity and thus confounds the interpretation of published data on clinical validity. Further testing in primary care clinics is needed to validate the accuracy of the clinician module. In addition, all published studies were conducted on children who had been pre-selected as having high-risk of autism. No studies on children from the general population have been published. Other limitations include differences that may occur between the testing environments of a structured clinical trial setting versus the home setting and lack of data on usability outside of a clinical trial. Evidence for the Canvas Dx has not directly demonstrated the test to be clinically useful, and a chain of evidence cannot be constructed to support its utility. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

CureSight™

The CureSight™ system is indicated for improvement in visual acuity and stereo acuity in individuals between the ages of 4 years and 9 years or younger with amblyopia, associated with anisometropia and/or with mild strabismus, having received treatment instructions (frequency and duration) as prescribed by a trained eyecare professional. CureSight™ is intended for both previously treated and untreated participants and is intended to be used as an adjunct to full-time refractive correction, such as glasses, which should also be worn under the anaglyph glasses during CureSight™ treatment. CureSight™ is intended for prescription use only, in an at-home environment.

The CureSight™ system is an eye-tracking-based system aimed for improving visual acuity and stereo acuity under dichoptic conditions. The technology is based on real-time eye tracking and separation of the visual stimuli presented on a monitor into two separate digital channels, one for each eye. Using this dichoptic method, any streamed video content can be tailored individually per eye and then presented simultaneously to each eye.

During a treatment session, the child wears the red-blue glasses while watching personally selected streaming videos (e.g., Disney, Netflix, Prime video, Hulu, History Channel, and National Geographic) from the computer touchscreen display. The streaming video is presented in different colors for each eye and altered by the software algorithm using embedded eye-tracking and image-processing sensors by blurring the images in the center of vision of the dominant eye, while the amblyopic eye receives normal, sharp images, thereby encouraging the visual system to integrate the visual information to have both eyes working together simultaneously. The cloud platform monitors in real-time patient compliance and progress and provides a treatment summary and progress report to the prescribing eye care provider. Treatment sessions are 90 minutes per day, 5 days a week for 16 weeks for an overall cumulative time of 120 hours. This treatment is seen as an alternative to conventional patching of the non-amblyopic eye.

The evidence includes one prospective, multicenter RCT (n=103 children aged 4 to ≤ 9 years with anisometropic, small-angle strabismic, or mixed-mechanism amblyopia). Wygnanski-Jaffe et al. (2022) randomly assigned 1:1 to either CureSight, a digital binocular, eye-tracking-based home treatment delivered through watching passive video streaming content (n=51) or eye patching of the non-amblyopic eye (n=52). Outcome measures performed at 4,8,12, and 16 weeks comprised the Amblyopia Treatment Study (ATS) Diplopia assessment, a Symptom Survey (five-question ocular symptom survey from the ATS Miscellaneous Testing Procedures Manual), and the blinded investigators performed distance visual acuity and stereoacuity testing chosen based on the participants' age at the time of enrollment. The primary effectiveness outcome was defined as the mean improvement from baseline in amblyopic eye visual acuity to week 16 across both study arms. The study met its primary effectiveness endpoint of noninferiority of improvement in amblyopic eye visual acuity in the CureSight treatment group compared to patching.

d-Nav® Insulin Management Program

d-Nav combines an FDA-cleared mobile app–enabled by artifical intelligence (AI) technology, and virtual clinical support to make autonomous adjustments to a patient's insulin prescription based on their historical and current glucose levels. The d-Nav technology calculates the next dose of insulin to aid in optimizing insulin management. The d-Nav Program is indicated for adults with type 2 diabetes who are injecting insulin.

The d-Nav Insulin Guidance System was evaluated in one multicenter, open-label RCT with 181 individuals who had uncontrolled type 2 diabetes. Participants were randomly assigned to either d-Nav and healthcare professional support (intervention group; n=93) or healthcare professional support alone (control group; n=88). The primary outcome of interest was to compare average change in HbA1c from baseline to 6 months. Safety was assessed by the frequency of hypoglycemic events. The mean decrease in HbA1c from baseline to 6 months was 1.0% in the intervention arm and 0.3% in the control arm (P<0.0001). The difference in frequency of hypoglycemic events between the groups was not statistically significant. Current data are limited by a single study with small sample size and long-term data of net health outcomes are unreported. The evidence is insufficient to determine that the technology results in an improvement in net health outcomes.

Drowzle®

Drowzle is a mobile software used to collect symptom data for sleep apnea risk, including severity of daytime sleepiness and personal chronic disease risk factors. Drowzle also records sleep breathing patterns and sends the sound files to secure servers in the cloud. Drowzle then analyzes and interprets the sleep breathing results, along with the profile data provided by the individual, to measure and track sleep-related health risks over time.

Drowzle is indicated to record a patient's respiratory pattern during sleep for the purpose of prescreening individuals for obstructive sleep apnea (OSA) syndrome. The device is designed for use in home-screening of adults with suspected possible sleep breathing disorders. Results are used to assist the healthcare professional in determining the need for further diagnosis and evaluation.

Narayanm et al (2019) performed a longitutional cohort study, participants (n=59) were observed in a sleep lab and evaulated via clinical polysomnography (PSG) to compare the Drowzle device and algorithm to the results of PSG. The authors report that Drowzle resulted in a 93.7% and 63.0% for sensitivity and specificity, respectively. Also, Drowzle found negative predictive value of 89.5%, and positive predictive value of 75.0%, in the detection of moderate and severe OSA among individuals compared to PSG results.

EndeavorRx™

EndeavorRx is video-game–based software intended to provide therapy for attention deficit-hyperactivity disorder (ADHD) or any of its individual symptoms as an adjunct to clinical supervised treatment. It is indicated for children ages 8 to 12 years old with primarily inattentive or combined-type ADHD, who have a demonstrated attention issue and intended to improve attention function as measured by computer-based testing.

The evidence for Endeavor Rx includes a double blind RCT of 348 individuals aged 8 to 12 years who received treatment with the AKL-TO1 (earlier non-prescription version) video game, N= 180, compared with an inactive control digital intervention (N=168 children with ADHD)  over 4 weeks. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. The single RCT that has been identified compared outcomes of the predecessor of the FDA-cleared EndeavorRx® (AKL-T01) with a word game that targeted different cognitive abilities. Although the experimental treatment group had significantly greater improvement on a computerized test of attention, both the experimental and control groups improved to a similar extent on parent and clinician assessments. The clinical significance of an improvement in a computerized test of attention without a detectable improvement in behavior by parents and clinicians is uncertain. A number of questions remain concerning the efficacy of this treatment, and additional studies to assess the effect of the digital therapy in adolescents and in children on stimulant medication are ongoing or have recently been completed. At this time, the digital therapy cannot be recommended as an alternative or adjunct to established treatments. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Freespira®

Freespira is intended for use as a relaxation treatment for the reduction of stress by leading the user through guided and monitored breathing exercises. The device is indicated as an adjunctive treatment of symptoms associated with panic disorder (PD) and/or posttraumatic stress disorder (PTSD), to be used in home sessions daily for 4 weeks under the supervision of a licensed healthcare provider, together with other pharmacological and/or nonpharmacological interventions.

Freespira was evaluated in two small cohort studies.  Tolin et al. (2017) evaluated adults with panic disorder in a multicenter, single-arm trial (N=69) who received 4 weeks of Capnometry Guided Respiratory Intervention (CGRI) using Freespira, which provides feedback of end-tidal CO₂ (PetCO₂) and respiration rate (RR) via a custom sensor device. This intervention is delivered via home use following initial training by a clinician and provides remote monitoring of client adherence and progress by the clinician. Outcomes were assessed immediately post-treatment and at 2- and 12-month follow-up. CGRI was associated with a response rate of 83% and a remission rate of 54%, in addition to large decreases in panic severity. Similar decreases were found in functional impairment and in global illness severity. Gains were largely sustained at follow-up. PetCO₂ moved from the slightly hypocapnic range to the normocapnic range.

In 2020, Kaplan et al. evaluated a cohort study (N=51) at a single center for a 12-month period. In total, 45 (87%) completed the 4-week, twice-daily Freespira home device treatments and at least 15 of the 56 protocol-specified therapy sessions. By study-end (12 months) just 22 participants were available for complete analysis. Overall, the cohort's Panic Disorder Severity Scale (PDSS) score fell from a baseline median of 14.4 (standard deviation [SD]=3.8) to 4.4 (SD=4.5) at 12 months, and 82% of the cohort reported a Panic Disord Severity Scale decrease of ≥40% (clinically significant) whereas 86% were free from panic attacks.

The evidence for Freespira is limited by the lack of comparison groups, studies with small sample sizes, and loss to follow-up within the study population. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Halo™AF Detection System

Halo™AF Detection System is a wearable watch device indicated for use by individuals who have been diagnosed with or are susceptible to developing atrial fibrillation (AF) and who would like to monitor and record their pulse rhythms on an intermittent basis and alert their physicians of any detected irregular heart rhythms. This device monitors pulse rhythms for the detection of AF via a compatible Samsung smartwatch worn at night while the user is resting or on demand during the day. The software for this device is based on an algorithm that filters and detects irregular pulse rhythms that may be suggestive of AF from photoplethysmography (PPG) data. The recordings are analyzed by the LIVMOR Halo + Home Monitoring System™ tablet when connected to Wi-Fi. When a signal is suggestive of AF, the rhythm is flagged for physician review through a cloud-based portal. It is available by prescription only.

The Halo™ AF Detection System has not been validated for use with any other pulse-monitoring system. Currently, only a retrospective propensity-matched cohort study is available to evaluate the efficacy of this system. Wang et al. followed 125 individuals with AF for 90 days to compare individuals using wearables to monitor heart rate and rhythm to 500 individuals with AF who did not use wearables. The study found that prior to propensity matching, those who used wearables were, on average, significantly younger (P<0.001) and healthier (composite score of congestive heart failure, hypertension, diabetes, prior ischemic event, vascular disease, age, and gender; P<0.001). After matching, study participants using wearables were found to have similar pulse rates to those who did not, but utilized significantly more healthcare. In particular, there was a significant difference in receipt of a cardiac ablation, with 17.6% (n=22) in the wearables group compared to 7.4% (n=37; P=0.001) having received an ablation. The study authors concluded that additional, properly designed evaluations of wearable technology's impact on health outcomes and healthcare use are needed.

Home Vision Monitor®

Home Vision Monitor, also referred to as myVisionTrack, is intended for the detection and characterization of central 3 degrees metamorphopsia (visual distortion) in individuals with maculopathy, including age-related macular degeneration and diabetic retinopathy, and as an aid in monitoring progression of disease factors causing metamorphopsia. It is intended to be used by individuals who have the capability to regularly perform a simple self-test at home. The device is not intended to diagnose; diagnosis is the responsibility of the prescribing eye care professional.

Korot et al. (2021) analyzed the Home Vision Monitor in a cohort study of 417 individuals to evaluate uptake and engagement of the application, but no published studies reported on clinically meaningful outcomes related to use of the Home Vision Monitor device.

Insulia® Diabetes Management Companion

Insulia is a prescription software program via a mobile app or web portal that recommends basal insulin doses for adults with type 2 diabetes treated with long-acting insulin analogues (e.g., Lantus, Levemr, Toujeo, Tresiba, and Basaglar) as an aid in the management of diabetes based on the treatment plan created by a healthcare provider. The Insulia app's functionality includes the secure capture, storage, and transmission of the patient's diabetes-related data via a web portal. This software purports to allow for educational coaching messages to be given, and physicians can remotely monitor a patient's progress and adjust their treatment plan as needed.

INVU™ by Nuvo™

INVU™ by Nuvo™ is a maternal-fetal monitor that noninvasively measures and displays fetal heart rate (FHR), maternal heart rate (MHR) and uterine activity (UA). The INVU Sensor Band^TM acquires the fetal heart electrocardiogram and maternal heart electrocardiogram signals from abdominal surface electrodes and the fetal phonocardiogram and the maternal phonocardiogram signals from surface acoustic sensors. The FHR, MHR, and UA tracings are derived from these signals and presented.

INVU™  is indicated for use by pregnant women who are in their 32nd week of gestation (or later), with a singleton pregnancy, and intended for antepartum fetal surveillance (i.e., non-stress testing) by healthcare professionals in healthcare facilities and by the expectant individuals in their home, on the order of a physician. This system is not intended to prevent the onset of preterm labor nor will it prevent the occurrence of preterm birth.

A pivotal clinical study was performed to collect and digitally record uterine activity data from INVU™ by Nuvo™, the uterine activity gold standard (IUPC) and the uterine activity standard of care (TOCO) to provide evidence of safety and agreement between INVU™ by Nuvo™ and both the gold standard and the standard of care devices for the assessment of uterine activity. The study was divided into two phases consisting of a training phase (N=40) and a validation phase (N=80).

The results indicate that the INVU™ by Nuvo™ platform provided reliable UA data by demonstrating a comparable performance of the device to that of the gold standard, IUPC. INVU™ met the performance goal of achieving a lower 95% confidence bound of the positive percent agreement that is greater than 75%. INVU™ presented a positive percent agreement of 84.80% (95% CI: [81.58%; 88.02%]) compared to IUPC. In comparison, the TOCO device showed positive percent agreement of 37.50% (95% CI: [28.23%;46.77%]). INVU™ presented a false-positive rate of 24.28% (95%Cl: [20.46%;28.11%]) compared to IUPC, while the TOCO device showed a false-positive rate of 10.69% (95%Cl [5.65% ;15.72%]). The investigators report the data demonstrated that the product is comparable to the standard of care TOCO device and meets the required accuracy for its intended use in populations of pregnant women aged between 18 and 50 of at least 32 weeks gestation. No device-related adverse events were observed during the validation study.

leva® Pelvic Digital Health System

leva® Pelvic Digital Health System is a prescription-only, battery powered, intravaginally used wand device with motion sensors that facilitates pelvic floor exercise training to strengthen pelvic floor muscles through rehabilitation and training of weak pelvic floor muscles for the treatment of stress, mixed, and mild to moderate urgency urinary incontinence in women, including overactive bladder. The device may be used repeatedly by a single user. The device interacts with the user via a smart phone app and Bluetooth technology, enabling the user to visualize their exercise performance to help the patient target the muscles used to help maintain continence. The app provides programmed coaching sessions to optimize pelvic floor muscle training. Individuals perform exercises while standing twice daily session for several minutes for up to 12 weeks. These sessions can be tracked, reviewed, and shared with the prescribing healthcare professional.

Rosenblatt et al. (2019 performed a single-center, prospective, open-label study (N=23) on premenopausal women with stress or mixed, urinary incontinence (UI) who received treatment with the leva® Pelvic Digital Health System. Individuals performed pelvic floor muscle (PFM) exercises while standing with use of the accelerometer-based system twice daily for 6 weeks. Each training session was five repetitions of 15-second PFM contraction followed by 15-second relaxation over 2.5 minutes. These sessions took place in an outpatient clinic and were supervised by the same research assistant. Pelvic floor angle measurements at rest, with strain, and with PFM contraction were taken at baseline, and then weekly for 6 weeks. Each participant also answered the following validated questionnaires: Urogenital Distress Inventory (UDI-6), which measures the severity of urogenital complaints; Incontinence Impact Questionnaire (IIQ-7), which measures the impact of UI on daily activities; and Patient's Global Impression of Severity (PGI-S). At 3 and 6 weeks, the participants also completed the Patient's Global Impression of Improvement questionnaire, and at 6 weeks the participants indicated user-friendliness on a scale of 0 to 10 (easiest to impossible). Results demonstrated the pelvic floor angle at maximal effort contraction increased by 16° from 65.1° at baseline to 81.1° at 6 weeks (P<0.0001). The pelvic floor angle upon bearing down reduced from 48.3° at baseline to 43.7° (P=0.0043). The mean maximum duration of continuous voluntary PFM contraction increased by 174.8 seconds from baseline to 6 weeks (P< 0.0001). The maximum number of contractions performed within 15 seconds increased by 3.7 repetitions from enrollment to the study endpoint (P<0.0001). Participants also reported decreasing scores on the UDI-6, IIQ-7, and PGI-S from baseline to 6 weeks, indicating improvements in symptom severity and quality of life. Limitations of this study were small sample size, no comparison group, and regular interaction with a research assistant may have resulted in biases in subjective improvement reported by the participants and may not be generalizable to the same population during at home use. Longer follow-up is also needed to see if the reported improvements are sustainable.

Weinstein et al. (2022) reported on a multicenter RCT comparing an intravaginal motion-based digital therapeutic device for pelvic floor muscle training (PFMT) (intervention group) with PFMT alone (control group) in women with stress or mixed UI (N=77) with final analysis of 61 participants (29 in intervention group and 32 in control group) that showed no statistical difference in primary outcomes (scores on Urinary Distress Inventory or Patient Global Impression of Improvement).  Scores on the Pelvic Organ Prolapse and Colorectal-anal Distress Inventories and Pelvic-Floor-Impact Questionnaire did improve significantly more in the intervention group than the control group. The median number of stress UI episodes decreased more in the intervention group than the control group. The trial was prematurely terminated due to device technical considerations. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. Additional evidence may be emerging.

MindMotion™ GO

MindMotion™ GO is a telerehabilitation program used in stroke recovery or brain injury that uses video games in combination with the Microsoft Kinect v2 and Leap Motion controller that supports the physical rehabilitation of adults in the clinic and at home. The software was designed by neuroscientists to promote certain therapeutic movements to aid in the restoration of motor function to maximize an individual's recovery potential and includes rehabilitation exercises for the upper extremity, trunk, and lower extremity. There are currently no available published peer-reviewed studies on MindMotion™GO.

My Dose Coach™

My Dose Coach is indicated for single use outside the clinic setting for individuals previously diagnosed with type 2 diabetes who have been prescribed a once-daily long-acting basal insulin. My Dose Coach is intended as an aid to the patient to provide dose suggestions based upon the healthcare provider's (HCP) independent professional judgment. Before My Dose Coach can be initiated, the HCP configures the dose instructions for the specific individual and activates the application using specific instructions. The application uses the dose plan instructions provided by the individual's HCP to provide dose suggestions of once-daily long-acting basal insulin (i.e. basal insulin titration) that are based on the patient's FBG as well as hypoglycemia occurrence.

The evidence includes one prospective single-arm, pilot study (N=158, aged 18-75 years) with an HbA1c >7% (mean at baseline, 9.6%) who used the My Dose Coach™ app programmed according to the patient profile suggesting optimal basal insulin titration dosing using fasting self-measured plasma glucose and hypoglycemia data with 16 weeks of follow-up. Results demonstrated in the 141 participants who completed the study a mean reduction in HbA1c of 1.97% from baseline (P<0.001), which was statistically significant. The predefined glycemic target of 90 to 130 mg/dL was achieved in 58.9% of the participants within 66 days with no severe hypoglycemia events. Limitations include a single-center study, with no control or comparator arm, and longer term follow-up is needed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

NightWare™

NightWare is a mobile application that uses a proprietary Apple smartwatch to monitor motion and heart rate data to detect the occurrence of nightmares. The device arouses the wearer by vibrating with the intention for the temporary reduction of sleep disturbance related to nightmares in adults 22 years or older who suffer from nightmare disorder or have nightmares from post-traumatic stress disorder (PTSD). The device provides gentle vibration through touch based on an analysis of heart rate and motion during sleep. Currently, this software is only available for use in the United States by the military and veteran population, and there is a paucity of published peer-reviewed evidence evaluating efficacy.

Parallel™

Parallel, a digital program, uses cognitive behavioral therapy (CBT) to reduce the severity of symptoms for irritable bowel syndrome (IBS). It is intended to be used concomitantly with other IBS treatments to treat adults, 22 years or older, for up to 3 months.

Everitt et al. (2019)  evaluated Parallel in a three-arm RCT in which 558 participants were enrolled into either a telephone-delivered CBT (TCBT; n=186) group, web-based CBT (WCBT; n=185) group with minimal therapist support, or treatment as usual (TAU, n=187). Both of the intervention groups continued to also receive treatment as usual. The primary outcomes were IBS Symptom Severity Score (IBS-SSS) and Work and Social Adjustment Scale (WSAS) at 12 months. At completion of the study,  27% of the TCBT arm, 73% of the WCBT arm, and 30% of the TAU group were lost to follow-up. Of the remaining study participants, compared with TAU, IBS-SSS and WSAS scores were significantly lower in the TCBT group (both scores P<0.001) and the WCBT group (P=0.002 and P=0.001, respectively) at 12 months. The study was limited by a substantial loss to follow-up and comparisons to in-person CBT are lacking.

Everitt et al. (2019b) conducted a 24-month follow-up to the prior trial, of which 58% (n=323 of the original 558 participants remained). At 24 months the IBS-SSS score was significantly lower in the TCBT group (P=0.002) relative to TAU but the differences in the WCBT group were not sustained (P=0.33). Similarly, the mean WSAS score was lower in the TCBT group (P<0.001) but differences in the WCBT group fell to marginal significance (P=0.036) relative to the TAU group. Continued substantial loss to follow-up precludes firm conclusions regarding the efficacy of the application to be established.

Regulora®

Regulora is a self-administered prescription digital therapeutic (PDT) available on Apple or Android devices to provide gut-directed hypnotherapy for adults 22 years of age and older who have been diagnosed with IBS. Regulora is indicated as a 3-month treatment for individuals with abdominal pain due to IBS and is intended to be used together with other IBS treatments. There is no published peer-reviewed evidence evaluating the efficacy of Regulora.

RelieVRx

RelieVRx is indicated as a prescription-use, in-home use immersive virtual reality system intended to provide adjunctive pain relief treatment based on CBT skills for individuals aged 18 and older with a diagnosis of chronic low back pain, defined as moderate to severe pain that has lasted longer than 3 months.

Garcia et al. (2021) performed the only RCT for RelieVRx, which included 179 individuals (76.5% female, 90.5% Caucasian) with self-reported low back pain for a duration of 6 months or more with average pain intensity of 4 or >/10 and were randomly assigned 1:1 to a 56-day EaseVRx program, or a sham VR headset. The primary outcome was the effects of EaseVRx versus the Sham VR representing change in average pain intensity and pain-related interference with activity, stress, mood, and sleep from baseline to end of treatment at 56 days. Change was measured using the Defense and Veterans Pain Rating Scale (DVPRS), scale going from 0 (no pain) to 10 (worst pain), and the DVPRS interference scale (DVPRS-II), with 0 being does not interfere and 10 equaling completely interferes. Twice-weekly surveys were obtained with a final survey at treatment completion. Results demonstrated that user satisfaction ratings were higher for EaseVRx versus Sham VR (P<0.001). EaseVRx was superior to Sham VR for all primary outcomes with greater reductions in average pain intensity and pain-related interferences with activity, mood, and stress (highest P value=0.009).  Between-group comparisons for physical function and sleep disturbance demonstrated superiority for the EaseVRx versus the Sham VR (P=0.022 and 0.012, respectively). However, pain catastrophizing, pain self-efficacy, pain acceptance, and prescription opioid use (morphine milligram equivalent) did not reach statistical significance for either group.

Use of over-the-counter analgesic use was reduced for EaseVRx (​P<0.01) but not for Sham VR. A 3-month follow-up study by the same authors (Garcia et al., 2022) analyzed data for 188 participants who reported at 1, 2, and 3 months time intervals post the original 56-day end of treatment.  All participants (n=188) with baseline data from the previous study, 168 of which completed the 56-day treatment and remained blinded during this follow-up. Of those 168 participants, at least 20 did not complete their surveys at month 1, 2, and 3, but were still included in the dataset analysis. The researchers were unblinded during this 3-month follow-up.

ReSet™

ReSET is a mobile device software application indicated as a 12-week (90 days) prescription-only treatment intended to increase an individual's abstinence to substance use disorder and increase retention in the outpatient treatment by providing CBT, as an adjunct to outpatient treatment, for individuals 18 years or older who are currently under the supervision of a clinician.

For individuals with substance use disorders other than opioid use disorder who receive a prescription digital therapeutic, the evidence includes one pivotal RCT and secondary analyses of data from the trial. Relevant outcomes are symptoms, morbid events, change in disease status, quality of life, and medication use. Mobile digital technology is proposed as an adjunct to outpatient treatment; however, there are a number of limitations in the current evidence base that limit any conclusions regarding efficacy. The RCT assessed the combined intervention of computer-based learning and a reward for abstinence. Because reward for abstinence alone has been shown to increase both abstinence and retention, the contribution of the web-based program to the overall treatment effect cannot be determined. The treatment effect on abstinence was not observed at follow-up, raising further questions about the relative effects of the rewards and the web program. Whereas the RCT reported a positive effect on the intermediate outcome of retention, the relationship between retention and relevant health outcomes in this trial is uncertain. A retrospective secondary analysis of data from the trial reported an association between engagement with the app and abstinence at 9 to 12 weeks, but study design limitations preclude drawing conclusions from this study. Given these limitations, further studies in well-designed trials are needed to determine the effects of prescription digital therapeutics on relevant outcomes in individuals with substance use disorders. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

ReSet-O™

ReSet-O™ is a mobile device software application intended to increase retention of individuals with opioid use disorder (OUD) in outpatient treatment by providing CBT as an adjunct to outpatient treatment that includes transmucosal buprenorphine and contingency management for individuals 18 years or older who are currently under the supervision of a clinician.

For individuals with opioid use disorder who receive a prescription digital therapeutic, the evidence includes one pivotal RCT and analysis of data of more than 3000 individuals from the mobile app. Relevant outcomes are symptoms, morbid events, change in disease status, quality of life, and medication use. Mobile digital technology is proposed as an adjunct to outpatient treatment that includes transmucosal buprenorphine and contingency management; however, there are a number of limitations in the current evidence base that limit any conclusions regarding efficacy. The RCT did not meet a primary objective of longest days of abstinence. Although there was a positive effect on the intermediate outcome of retention, the relationship between retention and relevant health outcomes in this trial is uncertain. Retrospective observational studies found that participants who completed more modules with the mobile app had greater abstinence during weeks 9 to 12 and, in a subgroup of individuals who received a refill prescription, during weeks 21 to 24, but the retrospective design and lack of a control group with comparable motivation limits interpretation of these results. Given these limitations, future studies in well-designed trials are needed to determine the effects of prescription digital therapeutics on relevant outcomes in individuals with opioid use disorder. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

RevitalVision (NeuroVision, Inc.)

RevitalVision is a standalone therapeutic vision training software, FDA-approved treatment of amblyopia using an interactive computerized program in individuals 9 years or older. Through a series of training sessions, the product provides the user with a series of linear images oriented in vertical and horizontal planes on a video imaging screen that is designed to identify and correct visual dysfunction from reduced visual acuity by re-training the eye to use its optimal visual response in gaining an increased awareness of visual acuity. The device will analyze a user's visual acuity deficiencies and sets a program for the user to increase the demand on the visual system, resulting in an improvement of visual acuity. The device pre-programs a series of visual stimuli tasks and takes the user through a series of interactive functions in identifying various objects on the video screen; it is purported to aid in providing an environment that increases a visual response.

Somryst®

Somryst® is a digital therapeutic intended to provide a neurobehavioral intervention (CBT) in individuals 22 years of age and older with chronic insomnia. Somryst's has been evaluated in two RCTs.  Christensen et al. (2016) randomly assigned 1149 participants with insomnia and depression symptoms to receive Somryst's predecessor (SHUTi; n=574) or HealthWatch (an interactive, attention-matched, Internet-based placebo control program; n=575). The primary outcome of interest was depression symptoms at 6 months. At 6 weeks follow-up, 49% of participants were lost to follow-up and by 6 months the dropout grew to 64%. In the remaining study participants, at 6 months, SHUTi lowered depression symptoms compared to the HealthWatch (P<0.0001) and no adverse events were reported. Study limitations include a substantial loss to follow-up and a comparator group that is not commensurate to generally accepted standards of medical practice for treatment of insomnia.

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Ritterband et al. (2017) performed an RCT (n=303 self-diagnosed adults with chronic insomnia) and randomly assigned participants to SHUTi (n=151) or an online educational program with fixed (nontailored) information about insomnia (n=152). Results from the three primary sleep outcomes (Insomnia Severity Index, Sleep Onset Latency, and Wake After Sleep Onset) at 9 weeks, 6 months, and 1 year significantly favored the SHUTi cohort (P<0.001 for all three outcomes). All the data collected in this study were self-reported and as such may be subject to bias. Similar to the other published RCT, the comparator group did not receive standard of care medical treatment for insomnia; as such, Somryst's efficacy relative to generally accepted standards of medical practice cannot be established.